Apremilast in Paediatric Dermatoses - A Comprehensive Review.

Apremilast has recently garnered attention in the management of multiple dermatological conditions including psoriasis. The comparable effectiveness with immunosuppressive drugs and a favorable side effect profile makes the drug, a prudent alternative for managing a gamut of dermatoses. In this article, we have reviewed the literature on apremilast use in children. Copyright:

Introduction

Apremilast is the first selective phosphodiesterase 4 (PDE4) inhibitor approved in 2014 for moderate-to-severe plaque psoriasis and active psoriatic arthritis (PsA) in adults. The potential safety and tolerability profile of the drug makes it valuable for patients who do not tolerate or those who are unresponsive to conventional systemic agents, including those who are not candidates for biologics. As for pediatric psoriasis, there is limited evidence-based data and approved drugs, and standardized treatment guidelines are still lacking. In this scenario, explicit studies are warranted for the recommendation of the drug in the treatment of paediatric psoriasis. To date, there are few case reports sharing the experience on the use of apremilast in children, with psoriasis,[1] atopic dermatitis,[2] alopecia totalis[3] and vitiligo.[4] In this article, we provide a detailed review of literature for the use, safety and tolerability of apremilast in pediatric dermatoses studied to date.

Materials and Methods

A comprehensive English literature search across multiple databases (PubMed, EMBASE, MEDLINE, and Cochrane) for articles on the use of apremilast in children was done using the key words (both MeSH and non MeSH, alone and in combination) “phosphodiesterase-4 inhibitors”, “PDE-4 inhibitors” AND/OR “apremilast”, “paediatric psoriasis” AND/OR “childhood psoriasis”, “paediatric dermatoses” AND/OR “childhood dermatoses”, “atopic dermatitis”, “alopecia areata” and “vitiligo”. The levels of evidence and grade of recommendations have been delineated as per the criteria laid down by Strength of Recommendation Taxonomy (SORT) and Oxford Centre for Evidence-Based Medicine (CEBM) [Box 1-3].

Box 1

Strength of recommendation taxonomy (SORT) guidelines

A : Recommendation based on consistent and good-quality patient-oriented evidence B : Recommendation based on inconsistent or limited-quality patient-oriented evidence C : Recommendation based on consensus, usual practice, disease-oriented evidence, case series for studies of treatment or screening, and/or opinion

Box 3

The grade of recommendation based on the criteria set forth by the Oxford centre for evidence-based medicine (CEBM)

A=Consistent level 1 studies B=Consistent level 2 or 3 studies or extrapolations from level 1 studies C=Level 4 studies or extrapolations from level 2 or 3 studies D=Level 5 evidence or troubling inconsistent or inconclusive studies at any level

Results

Pharmacokinetics

Studies (in the adult population) show that the bioavailability of apremilast following oral administration of 20 mg is 73% and binding to human plasma proteins is 68% approximately.[56] Absorption is unaltered with food intake. The exact mechanism of action of apremilast in psoriasis is not yet clearly defined but it works intracellularly to interrupt the inflammatory cascade by inhibiting PDE4 and thus, increasing the levels of cyclic adenosine monophosphate (cAMP) having an antagonistic effect on the production of proinflammatory cytokines like TNF-α, IL-23 and IFN-γ.[7] The elimination half-life ranges from six to nine hours with the clearance being 36% lower in patients with PsA. The clearance is diminished by 47% in patients with severe renal impairment (an estimated glomerular filtration rate [eGFR] of less than 30 mL/min), warranting dose reductions while no other factors like age, gender, race/ethnicity or hepatic impairment have been found to influence the pharmacokinetics.

Adverse effects

The side effects associated with the use of apremilast are quite low. Gastrointestinal intolerance in the form of diarrhea and nausea is observed in the initial months as early as 2 weeks and is usually self-resolving within 1 month.[8] Headache and nasopharyngitis are other side effects reported in trials.[8] Rare potential warnings include depression and weight loss.[9] Concomitant use of apremilast with strong CYP 450 enzyme inducers (like rifampin, phenytoin) is not recommended due to a reduction in the effectiveness.

A phase 2 open-label study[10] conducted in children with moderate to severe plaque psoriasis evaluated the pharmacokinetics and safety profile of apremilast in paediatric patients. The pharmacokinetics modeling and non-compartmental analysis showed that weight-based dosing of apremilast in children provides exposure comparable to that achieved with 30 mg twice daily of apremilast in adults. The adverse effects reported were nausea (52.4%), headache (45.2%), abdominal pain (42.9%), nasopharyngitis (38.1%), diarrhoea (35.7%) and vomiting (31%). Nausea, headache and diarrhoea occurred mostly in the first month of treatment, thereby resolving within 3 days. In the laboratory patients rarely developed parametersthat raised blood eosinophil count and proteinuria. The taste of the tablet was liked as “very much” (45.2%) or “a little” (14.3%).

The search for articles regarding use of apremilast in paediatric dermatoses yielded one phase 2 open-label study[10] in children with moderate-to-severe plaque psoriasis and a few case reports one each in paediatric psoriasis,[1] atopic dermatitis (AD),[2] alopecia totalis[3] and vitiligo.[4]

Psoriasis

In the study,[10] patients with plaque psoriasis received apremilast twice daily without titration for 2 weeks followed by a 48 weeks extension period in two groups (group 1 [age 12-17 years; weight ≥35 kg]: apremilast 20 or 30 mg and group 2 [age 6-11 years; weight ≥15 kg]: apremilast 20 mg). Post-treatment follow-up was done for 52 weeks. The improvement in Psoriasis Area Severity Index (PASI) score was observed as early as week 2. The mean percentage change from baseline in PASI score was –69.6 (standard deviation [SD], 19.5) for adolescents treated with apremilast 20 mg, –66.5 (SD, 17.1) for adolescents treated with 30 mg and –79.3 (SD, 17.4) for children treated with apremilast 20 mg twice daily at week 16. The study supports the use of weight based dosing of apremilast in children and adolescents with moderate to severe plaque psoriasis although it is limited by the use of PASI score as the exploratory endpoint as it is not a validated measure in paediatric psoriasis and also children weighing less than 20 kg were not enrolled. Smith[1] reported a case of severe psoriasis involving 50% body surface area (BSA) and weighing 98.9 kg treated with oral apremilast 30 mg twice daily dose. Clinically significant improvement was observed after 1 month with a marked reduction in the plaque thickness, scaling, pruritus and erythema with continued improvement and no side effects at 6 and 9 months follow up visits. Evidence on the use of apremilast in pediatric psoriatic arthritis is lacking, and clinical trials are under way (results have not been published yet).[11] Based on the available evidence and results of the survey, a group of experts has opined that apremilast can be considered in paediatric patients with plaque psoriasis who are not responding to topical therapy. Regarding the dosing of apremilast in the paediatric age group, the experts commented that the dosage should be individualised.[12]

Atopic dermatitis

One case report published by Saporito et al.[2] describes the marked improvement in pruritus, inflammation and excoriation in an 8-year-old boy with severe AD within 2 weeks of apremilast 30 mg (once daily dose), who otherwise had marginal improvement with oral and topical immunosuppressives, and omalizumab.

Alopecia areata

One case report published by Chhabra et al.,[3] described the use of oral apremilast and platelet rich plasma (PRP) therapy in steroid resistant Alopecia totalis, in an 11 year-old boy. Both apremilast (30 mg in the morning and 10 mg in the evening) and PRP were continued for 6 months, and robust hair growth was observed.

Vitiligo

In a single case report by Hassanandani et al.,[4] a 13-year-old girl who presented with co-localised lesions of psoriasis and vitiligo, was successfully treated with oral apremilast 30 mg twice daily and NB-UVB (300 mJ/cm2) with a 20% increment twice weekly, for 12 weeks. PASI 75 was achieved at week 12 with a significant improvement in the Dermatology Life Quality Index. More than 50% repigmentation of the vitiligo patches was observed.

Active oral ulcers associated with Behcet's disease

A phase 3, multicenter, double-blind, randomised, placebo-controlled, parallel-group study, followed by an active treatment phase to evaluate the efficacy and safety of apremilast in children from 2 to less than 18 years of age with active oral ulcers associated with Behçet's disease (BEAN) is being performed, and the results are awaited.[13]

Scope in COVID 19 infection

In this era of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, there is a growing concern regarding the use of immunosuppressants which are critical for the management of inflammatory conditions like psoriasis and psoriatic arthritis. Very few studies[141516] have been suggested in favour of using apremilast during SARS-CoV-2 in patients with psoriasis. Apremilast has no effect on B and T cells, IgG and IgM secretion, but has a partially inhibitory effect on TNFα, interferon gamma, IL-17, and IL-23. Due to its immunomodulatory properties and the specific mechanism of action, apremilast does not favor infections or cytokine storms, and does not increase the risk of pulmonary fibrosis as well. It has been observed in various reports that apremilast did not increase the risk of severe COVID-19 in patients of psoriasis.[17] Therefore, apremilast can be used safely in the ongoing COVID-19 pandemic. Olisova et al.[18] have even suggested apremilast as a potential treatment option for COVID-19 taking into consideration its specific mechanism of action which acts against the mediators of the so called “cytokine storm”, but this conclusion requires further validation on large scale studies.

Discussion

The various studies on off label uses of apremilast mostly in adults have been reviewed by Maloney et al.[19] and Nassim et al.[20] The indications studied were notably alopecia areata, atopic dermatitis, aphthous stomatitis, chronic actinic dermatitis, Behçet's disease, hidradenitis suppurativa, nail and scalp psoriasis, palmoplantar psoriasis, cutaneous sarcoidosis, discoid lupus erythematosus, lichen planus, refractory erythema annulare centrifugum and rosacea. An ongoing phase III multicentre (BEAN) trial[13] to study the efficacy and safety of apremilast in children of 2 to 18 years of age with active oral ulcers associated with Behçet's disease is being performed. Vitiligo co-existent with psoriasis showed significant repigmentation in an adolescent girl with apremilast at a dose of 30 mg twice daily and NB-UVB combination therapy.[4] The conditions where apremilast has been tried in the paediatric age group have been summarised in Table 1.

Table 1

Apremilast in pediatric age group: Summary of levels of evidence and grade of recommendation

Indications where apremilast has been tried in pediatric age	SORT (Strength of recommendation taxonomy)	OCEBM (Oxford Centre for Evidence Based Medicine)	Grade of recommendation
Psoriasis	A	1b	A
Atopic dermatitis	C	5	D
Alopecia areata	C	5	D
Active oral ulcers associated with Behcet’s disease	Clinical trial in progress (evidence yet to be generated)
Vitiligo	C	5	D

Conclusion

To date the experience on the use of apremilast in adults and also in children in various approved and off label indications in dermatology provide us with the opportunity to choose a molecule having the advantages of relatively safe side effect profile, powerful immunomodulatory actions, lack of immunosuppressive activity, availability in the oral formulation and no requirement for routine laboratory monitoring. Further studies will add on to determine the best potential use of apremilast in dermatology, more so in the paediatric population and during the COVID pandemic.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Box 2

Levels of evidence as per the criteria set by Oxford centre for evidence-based medicine (CEBM)

1a=Systematic reviews (with homogeneity) of randomized controlled trials (RCT) 1b=Individual RCT (with narrow confidence interval) 1c=All or none. Met when all patients died before the Rx became available, but some now survive on it; or when some patients died before the Rx became available, but none now die on it. 2a=SR (with homogeneity) of cohort studies 2b=Individual cohort study (including low quality RCT; e.g., <80% follow-up 2c = “Outcomes” research; Ecological studies 3a=SR (with homogeneity) of case-control studies 3b=Individual case-control study 4=Case-series (and poor quality cohort and case-control studies) 5=Expert opinion without explicit critical appraisal, or based on physiology, bench research or “first principles”